These studies are directed at the elucidation of the biochemical determinants of drug action at the cellular level and the application of these insights to the therapy of malignant disease. This work encompasses the study of the in vitro uptake of antifolates, their intracellular metabolism, and their interaction with fluoropyrimidines. Secondly, we have studied the effects of 3-deazauridine on cytosine arabinoside activation and degradation, and the synergistic interactions of these agents. We have continued studies of the physiology of the pineal secretion, melatonin, and have demonstrated its suppressive effect on the progesterone and estrogen receptor content of the uterus. We have completed phase I studies of the new antitumor agent PALA (phosphono-N-acetyl-L-aspartic acid) and have found dose-limiting toxicity to gut and skin at 2000 mg/m2/d times 5d.